This invention describes novel methods of treating multiple drug resistance of refractory tumor cells in a patient in need of such treatment, said method comprising the combined use of (1) a P-gp inhibitor and (2) an antineoplastic agent.
Resistance to drug therapy thwarts the treatment of many diseases and infections, particularly cancer. A major cause for the observed resistance is the overexpression of transmembrane multidrug resistance transporters (MDR) responsible for pumping structurally diverse antitumor drugs from cells. By ejecting drugs from the cell, these transporter enzymes decrease exposure and hence efficacy. The resistance can be enhanced in mutated or induced cells, including cancer cells which commonly have elevated levels of these transporters.
Over-expression of P glycoprotein (xe2x80x9cPgp,xe2x80x9d 170-180 kDa), the product of the MDR1 gene, is the most commonly observed characteristic of multidrug resistant cells grown in vitro (Gottesman et al., 1993 Annu. Rev. Biochem 62:385-427; Schinkel et al, 1996, Shapiro et al., 1995, J. Biol. Chem 270: 16167-75 and in a number of tumors (Redmond et al., 1991, Decker et al., 1995).
Cancers which are known to exhibit drug resistance due to overexpression of the multiple drug transporter P-gp include adenocarcinomas derived from adrenal, kidney, liver, small intestine, and colon tissue (Gottes et al., 1987, New England J. Med 1388) pancreatic, carcinoid, chronic myelogenous leukemia in blast crisis, and non-small cell lung carcinoma. Examples of tumor cells which have the ability to overexpress the multidrug transporter protein upon selection by an antineoplastic agent include neuroblastoma cells, pheochromocytoma cells, multiple myeloma, adult acute lymphocytic leukemia cells, adult acute nonlymphocytic leukemia cells, nodular poorly differentiated lymphoma cells, breast cancer cells and ovarian and cervical cancer cells.
A large number of compounds that interact with the Pgp efflux pump have been identified and some are under development as drugs. These compounds have no common chemical structural features except for hydrophobicity. Some of them are positively charged at physiological pH (Chin, 1993). The early generation of modulators of Pgp, such as cyclosporin A (Sonneveld et al., 1992), verapamil (Watanabe et al., 1995) and quinidine (Wishart et al., 1992) failed to show clinical significance due to limited efficacy and their own dose related toxicity or profound alterations in pharmacokinetics when used in combination with anti-cancer drugs. The more recently developed modulators possess a higher affinity for Pgp, however their efficacy is still under clinical evaluation. Examples of this class include the cyclosporin A analog PSC 833 (Keller et al., 1992), the acridonecarboximide GF120918 (Hyafil et al., 1993), LY335979 (Slate, et al.1995), the triazinoaminopiperidine derivative S9788 (Merlin et al., 1995), a yohimbine analog, trimethoxybenzoylyohimbine (Pearce et al., 1989) and other compounds including MS-073 (Sato et al., 1991) and R-isomer of verapamil (Toffoli et al., 1995).
International Patent Publication Number WO92/11034 (published Jul. 9, 1992) (U.S. Pat. No. 5,416,091) discloses a method of inhibiting multiple drug resistance, by the concurrent administration of an antineoplastic agent and (inter alia) a potentiating agent of the formula: 
wherein the dotted line represents an optional double bond, Xxe2x80x2 is hydrogen or halo, and Yxe2x80x2 is hydrogen, substituted carboxylate or substituted sulfonyl. For example, Yxe2x80x2 can be, amongst others, xe2x80x94COORxe2x80x2 wherein Rxe2x80x2 is C-1 to C-6 alkyl or substituted alkyl, phenyl, substituted phenyl, C-7 to C-12 aralkyl or substituted aralkyl, 2-, 3- or 4-piperidyl or N-substituted piperidyl. Yxe2x80x2 can also be, amongst others, SO2Rxe2x80x2 wherein Rxe2x80x2 is C-1 to C-6 alkyl, phenyl, substituted phenyl, C-7 to C-12 aralkyl or substituted aralkyl. Examples of such potentiating agents include 11-(4-piperidyl-dene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine. Antineoplastic agents exemplified are: vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, and amsacrine.
SCH66336 is a tricyclic small molecule which was originally identified as a potent and selective inhibitor of the farnesyl protein transferase (FPT) enzyme. (U.S. Pat. No. 5,874,442; see also U.S. Pat. No. 5,719,148). The antitumor activity of SCH66336 includes inhibition of anchorage-indepent growth of a variety of human tumor cell lines in vitro and their growth as xenografts in immuno-compromised mice (Liu et al., 1998).
In view of the need for improved treatments for multiple drug resistance, novel methods of treatment would be a welcome contribution to the art. The present invention provides just such methods of treatment.
The present invention is based on the surprising discovery that SCH66336 and compounds in the same structural series are potent inhibitors of the P-gp transporter enzyme. The invention provides methods of treating multidrug resistance of refractory tumor cells in a patient (e.g., a mammal such as a human) in need of such treatment, said treatment comprising administering, concurrently or sequentially, an effective amount of (1) P-glycoprotein (P-gp) inhibitor, and (2) an antineoplastic agent. The methods of the present invention are particularly useful for the treatment of various cancers, especially adenocarcinoma cells derived from adrenal, kidney, liver, small intestine, and colon tissue, pancreatic, carcinoid, chronic myelogenous leukemia in blast crisis, non-small cell lung carcinoma, neuroblastoma cells, pheochromocytoma cells, multiple myeloma, adult acute lymphocytic leukemia cells, adult acute nonlymphocytic leukemia cells, nodular poorly differentiated lymphoma cells, ocular melanoma cells, skin melanoma cells, uterine melanoma cells, breast cancer cells and ovarian cancer cells, and metastatic cells.
In preferred embodiments, the P-gp inhibitor is combined with one of the following antineoplastic agents: gemcitabine, paclitaxel (Taxol(copyright)), 5-Fluorouracil (5-FU), cyclophosphamide (Cytoxan(copyright)), temozolomide, or Vincristine, docetaxel.
For instance, in a preferred embodiment, the present invention provides a method of treating multi-drug resistance comprising administering, concurrently or sequentially, an effective amount of (1) a P-gp inhibitor, and (2) gemcitabine. In a particularly preferred embodiment, the cancer to be treated is a pancreatic cancer.
In a particularly preferred embodiment, the present invention provides a method of treating multi-drug resistance, comprising administering, concurrently or sequentially, an effective amount of (1) the P-gp inhibitor SCH66336, and (2) an antineoplastic agent.